Notes
J . Org. Chem., Vol. 43, No. 24, 1978 4659
-
Synthesis of 4 (2-Hydroxyethylsulfonyl) - 1 naph.thalenesu1fonamide
Scheme I1 SCH2CH2CI
SCH:CH,
Guido H. Daub Department of Chemistry, Uniuersity of New Mexico, Albuquerque, New Mexico 87131
12
II
N
N
Thomas W. Whaley*
SCH = CH2
SCH=CH,
Organic and Biochemical Synthesis Group, Los Alamos Scientific Laborator)) University of California, Los A h m o s , New Mexico 87545 Received May 16, 1978
13
N
4-( 2-Hydroxyethyl~ulfonyl)-1-naphthalenesulfonamide (1, HO-ENS) has been identified as one of the principal metabolites formed when the bladder carcinogen 4-ethylsulfonyl-1-naphthalenesulfonamide(2, ENS) is ingested by
SOY
S03K 14
N
SC$H=CH2
E
If
40,Cl
SCH= CH2
*-"@@--e@@ I %"2
17
N
I
S02NH2
E
UNaOH (aq), ClCH,CH,OH, 90 "C. b SOCI,, CHC1,. CKOH, 95% E t O H , reflux. dClSO,H, CHC1,. e SOCl,, DMF. f E x c e s s NH,, CH,CN. g H,O,, H,O, HOAc, 90 "C. h NaOH, H,O.
mice.l This metabolite was identified on the basis of its chromatographic behavior; however, its synthesis has never been reported. We are reporting here the synthesis of 1 using an approach similar to1 the method reported for the synthesis of ENS2 and 15N-labeled ENS3 in our laboratory. 1-Naphthalenethiol (3)4 (Scheme I) was converted to 2(1-naphthy1thio)ethyl acetate (5) via 2-(l-naphthylthio) ethanol (4)5 in an overall yield of 75%. Sulfonation of the ester 5 was carried out using 1equiv of chlorosulfonic acid in dry chloroform to give the 4-(2-acetoxyethylthio)-l-naphthalenesulfonic acid (6) which was isolated as the sodium salt 7 in 68% yield. The acetoxy acid chloride 8 was prepared from 7 in 68% yield by the method of Bosshard et a1.,6 the chloro acid chloride 8a being isolated as a secondary product in 15% yield. The side product Sa probably arose from the hydroxyethyl derivative 7a present in the sodium salt 7, 7a being formed through partial ester exchange of the acetoxy group in the conversion of thie sulfonic acid 6 to the sodium salt 7 in the presence of ethoxi'de. Scheme I SCH2CH 20Ac
SCH2CH2R
1
3
S03Na
5
N
N
7,R=OAc
N
79,R
N
S02"2
S02N H2
9
N
1"
Lo\; I
N
N1 7 (SCHEME
=OH
n)
-
E-,
S0,CI R=OAc
80, R=CI
N
a NaOH ( a q ) , CXCH,C!H,OH, 90 "C. b Ac,O, NaOAc, 70 "C. cClSO,H, CHCI,. d N a O E t , E t O H . e SOCI,, DMF. fExcess NH,, CH,CN. g MCPBA., CH,Cl,. h HCI, H,O, E t O H , 60 "C. i N a O H , H,O.
0022-3263/78/1.943-4659$01.00/0
The reaction of the acid chloride 8 with excess ammonia in acetonitrile afforded an 89%yield of the desired sulfonamide 9, which was smoothly oxidized with rn-chloroperoxybenzoic acid (MCPBA) to the sulfone 10 in 84% yield.7 Attempts to oxidize 9 to 10 with hydrogen peroxide in aqueous acetic acid2 gave mixtures probably due to partial hydrolysis of the acetoxy group in 9. Hydrolysis of 10 with dilute hydrochloric acid in aqueous ethanol a t 60 "C readily afforded pure HO-ENS (1) in 95% yield. Hydrolysis of the sulfonamide 10 over a short period with aqueous base a t room temperature gave a mixture of several products, among which were the desired hydroxysulfonamide 1 and the vinylsulfone 17, the ester 10 being consumed completely within 1 min (TLC). Indeed, such behavior of 10 was not unexpected and has precedence in the literature.8 Furthermore, it was evident through TLC studies that the initial product formed in the reaction of 10 with aqueous base was the vinylsulfone 17 and that, over longer reaction periods, 17 was slowly being converted to HO-ENS (1) as would be expected.9 These preliminary findings led to the investigation of an alternate approach to the synthesis of 1 utilizing the Michael type addition of hydroxide ion to the sulfone 17 as shown in Scheme 11. The reaction of 2-( l-naphthylthio)ethano1(4)with thionyl chloride according to the method of Kirner and WindauslO afforded the chloride 11 in excellent yield. Dehydrohalogenation of 1 1 with alcoholic potassium hydroxide" afforded 1-naphthyl vinyl sulfide (12) in 81%yield; however, the attempted sulfonation of 12 with chlorosulfonic acid in chloroform gave only dark tars. Consequently, 1 1 was sulfonated directly with chlorosulfonic acid in chloroform to give the sulfonic acid 13 which was dehydrohalogenated with alcoholic potassium hydroxide to the potassium salt 14 in 70% overall yield. Conversion of 14 to the acid chloride 15 using thionyl chloride in DMF gave a product that was contaminated with several minor side products (TLC). This crude material afforded the amide 16 with ammonia in acetonitrile in 76% overall crude yield from 14. TLC showed the crude amide to contain several minor side products. Oxidation of recrystallized amide 16 with hydrogen peroxide in aqueous acetic acid12 afforded the vinylsulfonylsulfonamide 17 in 87% yield. Treatment of 17 with excess 5% aqueous sodium hydroxide gave the desired HO-ENS (1); however, minor impurities were present that were difficult to remove. l3C NMR and TLC studies showed conclusively that 1 could be prepared by the reaction of the vinylsulfone 17 with C 1978 American Chemical Society
4660 J . Org. Chem., Vol. 43, No. 24, 1978
Notes
A mixture of crude 7 (5.14 g, 14.8 mmol) and anhydrous DMF (30 mL) was placed in a 125-mL flask equipped with a magnetic stirrer and drying tube and was cooled in an ice bath. To this mixture was added 2.14 mL (29.6 mmol) of thionyl chloride and, after 5 min, the ice bath was removed and the mixture stirred a t room temperature for 2.5 h. Evaporation of the DMF a t reduced pressure (rotary evaporator) afforded 4.9 g of a tan oil which slowly turned t o an oily solid upon scratching. Trituration of this residue with 5 mL of CC14gave 1.74 g Experimental Section of 8: m p 80-82 "C; TLC R f 0.21 (benzene); lH NMR (CDC13) 6 Melting points and boiling points are uncorrected. Anhydrous 7.24-8.90 (6 H, m), 4.37 (2 H , t, J = 7.2 Hz), 3.36 (2 H , t, J = 7.2 Hz), solvents were prepared by drying over 3A molecular sieve. Infrared 1245 (AcO), 1163 2.02 (3 H, s); IR (KBr) 1730 (C=O), 1363 (AKSO~CI), (ArSOZCl), 1065 (AcOCH2) cm-'. spectra were recorded on a Perkin-Elmer Model 710 spectrophotometer. Proton magnetic resonance spectra were recorded on a Anal. Calcd for C14H&O&I: C, 48.77; H, 3.77. Found: C, 48.77; Perkin-Elmer Hitachi Model R-24 spectrometer using Me4Si as an H , 3.65. The mother liquor from the isolation of 8 contained two major internal standard, and I3C magnetic resonance spectra were recorded benzene]. components as indicated by TLC [8 (0.21) and 8a (0.80), on a Varian Model CFT-20 spectrometer. The 13C chemical shifts, reported as ppm downfield from MelSi, were referenced to the solvent The CCll was replaced with benzene, and the mixture was chromatographed on a silica gel (30 mm X 15 cm) using benzene as the eluent. peaks, MezSO-ds (39.6 ppm) or DCC13 (76.9 ppm). In those spectra The first fraction (110 mL) contained only material with R f 0.80 (0.73 run in aqueous solution, a DzO capillary containing 1%dioxane was used as a lock and external standard (dioxane: 67.4 ppm downfield g, 8a) and, after an intermediate fraction of 40 mL, a third fraction from Me4Si). Reactions were monitored and product purity checked (420 mL) contained only material with Rf 0.20 (1.72 g, 8). The total yield of 8 suitable for the next step thus amounted to 3.46 g (68%). by thin-layer chromato;:raphy on precoated silica gel 60 F-254 plates The material of R f 0.80 was identified as 4-(2-chloroethylthio)(EM Laboratories) using toluene-ethyl acetate ( l : l , v/v), unless 1-naphthalenesulfonyl chloride (8a) which, after crystallization from otherwise specified, as a developing solvent. The compounds and their CC14, gave pale yellow crystals: mp 108-109 "C; IR (KBr) 1364 (Arapproximate R f values were 1 (0.13, fluorescent), 3 (0.93), 4 (0.63), 5 (0.85),7 (0.68, EtOH-EtOAc, l : l ) , 8 (0.82; 0.21, benzene), 8a (0.93; SOZCl), 1161 (ArSOzCl)cm-I; l3C NMR (CDC13) 145.4, 136.8, 132.0, 0.80, benzene), 9 (0.501, 10 (0.39, fluorescent), 11 (0.93; 0.85, benzene), 129.8, 128.7, 127.8, 127.2, 125.0, 124.7, 120.2,41.1,34.1. 12 (0.84, benzene-cyclohexane, l : l ) , 14 (0.73, 95% EtOH-EtOAc, 1: Anal. Calcd for C 1 ~ H 1 & ~ 0 ~ CC, I z44.86; : H, 3.11. Found: C, 44.99; 1),15(0.84, benzene), 16 (0.70), and 17 (0.53, fluorescent). H, 3.08. 2-( 1-Naphthy1thio)ethyl Acetate (5). A 250-mL Erlenmeyer flask 4-(2-Acetoxyethylthio)-l-naphthalenesulfonamide(9). A solution of 3.03 g (8.79 mmol) of 8 in 36 mL of anhydrous acetonitrile equipped with a magnetic stirrer and condenser was charged with 12 g (75 mmol) of 1-naphthalenethiol (3),340 mL of water, and 60 mL was placed in a 50-mL flask equipped with a magnetic stirrer, gas inlet, and balloon. The reaction mixture was cooled in an ice bath, and anof 10% aqueous sodium hydroxide (-6 g NaOH). The mixture was cooled in an ice bath, and 6.8 mL (100 mmol) of 2-chloroethanol was hydrous NH3 was added through the gas inlet. A precipitate (NH4C1) formed immediately, the ice bath was removed, and the mixture was added. After stirring for 5 min, the ice bath was removed, the mixture stirred at room temperature for 2 h with periodic additions of NH3 was heated to reflux (1In), and a pale yellow oil separated. The cooled reaction mixture was extracted with ether (150 mL), and the organic sufficient to keep the balloon slightly inflated. The reaction mixture = 0.44 g, 93.5961, and the acetonitrile solution was layer was separated, washed with 10% aqueous NaOH followed by was filtered ("&I concentrated to 20 mL. Water was added to incipient turbidity, and water, and dried over anhydrous MgS04. Evaporation of the ether the solution was allowed to cool, during which time 9 separated as afforded 14.9 g (97%)of crude 2-(l-naphthylthio)ethanol(4)as a pale colorless plates (2.56 g, 89.5%),mp 142-143 "C. The sulfonamide 9 yellow oil (TLC R f :0.63 major, 0.93 trace): 'H NMR (CC14)6 6.95-8.60 exhibited another crystalline modification, m p 115-116"C, which (7 H , m), 3.93 (1 H, s ) , 3.57 ( 2 H , t, J = 6.4 Hz), 2.89 (2 H , t, J = 6.4 reverted to the higher melting form when its solution in 95% ethanol Hz). A mixture of crude 4,15 mL (159 mmol) of Ac20, and 0.2 g of anwas seeded with a crystal of 9: mp 142-143 "C, IR (KBr) 3410 ( N H ) , hydrous NaOAc was w,armed at 70 "C for 2 h with stirring in an Er3260 (NH), 1715 (C=O), 1325 (ArSOZNHz),1255,1225 (AcO),1190, 1145, 1130, 1060 cm-'; 'H NMR (acetone-&) 6 7.54-8.93 (6 H, m), lenmeyer flask equipped with a magnetic stirrer, condenser, and 6.72 (2 H, s), 4.31 (2 H , t, J = 6.4 Hz), 3.43 ( 2 H, t, J = 6.4 Hz), 1.97 (3 drying tube. After the mixture was stirred for an additional 13 h at H , s); 13C NMR (MezSO-de) 170.4, 139.6, 136.9, 131.5, 128.1,127.7, room temperature, 50 inL of water was added and stirring was con127.3, 126.4, 126.1, 124.5, 122.3, 61.9. 30.4, 20.7. tinued for an additional 2 h at room temperature. The yellow oil which Anal. Calcd for C14HljN0&: C, 51.69; H , 4.62: N, 4.31. Found: C, separated was extracted with ether (100 mL), and the ether layer was 51.70; H, 4.54; N, 4.21. washed successively with 5% NaHCOs and with water and was dried 4-(2-Acetoxyethylsulfonyl)-1-naphthalenesulfonamide (lo), over MgS04. The ether was removed and the product distilled to give A solution of 3.25 g (10 mmol) of 9 in 450 mL of anhydrous CH2C12 2-(l-naphthylthio)ethylacetate (5) as a colorless liquid, bp 142-146 was added dropwise over a period of 1 h to a cold (ice bath) stirred "C (0.1 mm) (13.8 g, 75% overall): TLC R f 0.85; 'H NMR (CC14)6 solution of 4.5 g (22 mmol) of 85% rn-chloroperoxybenzoic acid in 100 7.10-8.63(7H,m),4.14(2H,t,J=6.8Hz),3.04(2H,t,J=6.8Hz), mL of dry CHzCIz. The ice bath was removed after an additional 30 1.83 ( 3 H , s); IR (neat) 1737 (C=O), 1243 cm-' (AcO); I3C NMR min of stirring, and stirring was continued at room temperature for (CDC13) 170.0, 133.5, 1.32.7, 131.7, 129.0, 128.2, 127.5, 126.1, 125.8, another 2 h, after which time TLC showed the absence of 9 and the 125.1. 124.6, 62.4, 32.4, 20.2. Anal. Calcd for C14H1402S: C, 68.26; H, 5.73. Found: C, 68.22; H, presence of 10 as a fluorescent spot at R f 0.39. The reaction mixture 5.80. was extracted twice with 5% NaHC03 (as) and once with water. After Sodium 4-(2-Acetoxyethylthio)- 1-naphthalenesulfonate (7). drying the organic layer over anhydrous MgSO4, the CHZC12 was reA solution of 12.3g (50 mmol) of 2-(l-naphthylthio)ethylacetate (5), moved on a steam bath, and the residue was crystallized from 95% bp 142-146 "C (0.1 mm), in 50 mL of dry CHCI3 was placed in a ethanol to give 3.01 g (84%) of 10 as colorless prisms: mp 172-173 "C; 125-mL Erlenmeyer flask equipped with a magnetic stirrer, addition IR (KBr) 3380 (NH),3270 (NH), 1725 (C=O). 1335 (ArSOzR), 1312 funnel, condenser, and drying tube. The reaction mixture was cooled (ArSOZNHz), 1285,1235(AcO), 1185,1155 (ArS02R),1120cm-l; 13C NMR (Me2SO-dG) 169.7,145.5,138.8,129.4. 129.3,128.7,128.5,126.7. in an ice bath, and a solution of 5.8 g (50 mmol) of chlorosulfonic acid in 85 mL of anhydrous chloroform was added dropwise over a period 125.2, 124.9, 58.7, 54.6, 19.9. of 1.5 h. The mixture was stirred in the cold for an additional 2 h, after Anal. Calcd for C14H15NOsS2: C, 47.05; H. 4 23; N.3.92. Found: C, which time the chlorof(1rm was removed on a rotary evaporator, and 47.07; H , 4.34; N, 3.95. the viscous oily product was dissolved in 100 mL of 95% ethanol. This 4-(2-Hydroxyethylsulfonyl)- 1- n a p h t h a l e n e s u l f o n a m i d e solution was neutralized to pH 7 (indicator paper) by the addition of (HO-ENS) (1).T o a warm, stirred solution of 1.07 g (3 mmol) of 10, a solution of sodium ethoxide in ethanol, during which time the salt mp 172-173 O C , in 50 mL of 95% EtOH was added 50 mL of 5% separated as colorless plates. After cooling in an ice bath, the salt was aqueous HCI. The solution was heated at 60-65 "C for 2.5 h, at the end collected, washed with 95% ethanol, and dried for 15 h a t 120 "C in of which time TLC showed that 10 had been completely converted an evacuated desiccator to give 11.14 g of sodium 4-(2-acetoxyethylto 1. The reaction mixture was cooled, and the solvent was removed thio)-1-naphthalenesulfonate(7). An additional 0.8 g was obtained under reduced pressure on a rotary evaporator. The crystalline residue was triturated with water, filtered, washed with water, and dried in from the mother liquor for a total yield of 68%: TLC R f 0.68 (EtOHan evacuated desiccator to afford 0.90 g (95O10) of HO-ENS (1) as EtOAc, 1:l); IR (KBr) 3400 (OH), 1740 (C=O), 1200 (br, AcO, Arcolorless crystals, mp 208-209 "C. Recrystallization from 95% EtOH SO:1Na), 1060 (ArSOZNa) cm-l. gave an analytical sample as colorless prisms: mp 208-209 "C; IR 4-(2-Acetoxyethylt hio)-I-naphthalenesulfonylChloride (8) (KBr) 3570 (OH), 3420 ( N H ) ,3290 (NH), 1325 (ArSOZR),1310 (Arand 4-(2-Chloroethylthio)-l-naphthalenesulfonyl Chloride (8a).
aqueous base, as well as by the reaction of aqueous base with the ester 10 via the viinylsulfone 17; however, in each of these cases, the product is, more difficult to purify than that obtained from the hyd!rolysis of 10 with aqueous alcoholic hydrochloric acid.
Notes SO2NHz),1290,1190,1165 (ArSOZR),1140 (ArSOZNHz),1120cm-'; 13C NMR (MezSO-ds) 145.0,139.3,129.1,129.0,128.4,126.5,125.2,
124.9,58.1,55.2. Anal. Calcd for C ~ ~ H ~ ~ NC, O 45.71; ~ S Z H, : 4.13.Found: C, 45.70; H, 4.24. 2 4 1-Naphtha1enethio)ethylChloride (1 1). T o a stirred solution of 4 (11.9g, 58 mmol) in 5 mL of dry CHC13 was added dropwise (10 min) a solution of 4.35mL (59.8mmol) of SOC12 in 5mL of dry CHC13. The reaction mixture was warmed to 40-50 "C for 5 rnin and then stirred for an additional 10 min a t room temperature, at which point the reaction was complete (TLC). The excess CHC13 and SOClz were removed a t reduced pressure, and the residual oil amounted to 12.9 g (quant): IR (neat) 30:iO (CHZCl), 1500,1380,1210,1200 cm-'; 'H (7 H, m), 2.81-3.51(4H, m). NMR (CC14)6 6.92-8.40 1-NaphthylvinylSulfide (12).T o a stirred solution of 10.6g (47.6 mmolj of 11 in 15 mL of 95% EtOH was added a solution of 3.3g of KOH (85%) in 15 mL of 95% EtOH. The mixture was stirred under reflux for 2.5h, after which time 11 was completely consumed (TLC). The reaction mixture was cooled and the precipitated KC1 filtered (3.3g, 44mmol). The ethanol was removed on a steam bath, water was added, and the insoluble oil was extracted into ether. The ether solution was washed three times with water and dried over MgS04. The ether was removed and the residue distilled at reduced pressure, affording 7.12g (81%)of 12 as a colorless liquid: bp 106-108"C at 0.35 mm; IR (neat) 3080,1720,1580,1560,1500,1380,1260,1200,1020, cm-?; 'H NMR (CC14)6 6.95-8.20 (7 H, m), 6.26(1 H, 975,955,870 = 16 Hz), 5.04(1H, d, Jcis = 10 Hz), 4.90(1 d of d, J,i, = 10Hz, JtranS H, d, Jtrans = 16 Hz); '"C NMR (CDC13) 133.9,133.0, 131.9,130.9,
130.3, 128.7,128.4,126.6,126.2,125.6,125.2,114.3. Anal. Calcd for C12HlOS: C, 77.42;H, 5.38.Found: C, 77.31;H, 5.38. Potassium 4-(Vinyl1thio)-l-naphthalenesulfonate (14). T o a cold (ice bath) stirred solution of 12.9g (58.0mmol) of crude 11 in 65 mL of dry CHC13 was added dropwise 6.76g (58.0mmol) of ClS03H in 95 mL of dry CHC13. The solution turned a pale yellow-green, and after 5 min a colorless solid separated. The addition was complete in 50 min, and the reaction mixture was stirred for an additional 30min. The colorless solid was collected, washed with cold CHC13, and dried at 50 "C a t reduced pressure to give 13.09g (75%) of 4-(2-chloroethy1thio)-1-naphthalenesulfonicacid (13),mp 122-128 "C. The crude acid 13 was directly dissolved in 65 mL of 95% EtOH and to this solution was added a solution of 6 g of KOH (85%) in 65 mL of 95% EtOH. The resulting slurry was stirred a t reflux for 2 h, during which time an additional 30 mL of 95% EtOH was added to aid stirring (TLC The reaction showed a single spot at R f 0.73,95%EtOH-EtOAc, 1:l). mixture was cooled and the precipitate was collected, digested with hot 9596EtOH, filtered (to remove KCl), and allowed to cool, whereupon 14 separated as glistening plates (4.31g). An additional 1.20g of 14 was obtained from the mother liquor. The solid presumed to be KC1 from the original digestion with 95% EtOH contained additional 14.This was dissolved in hot water and, upon cooling, an additional 4.23g of 14was obtained to make the total yield 9.74g (70%).A small sample was recrystallized from 95% EtOH to give an analytical sample of 14 as glistening colorless plates: IR (KBr) 3570 (OH), 3470,1640, (ArS03-.H20), 1160 (ArS03-.H20), 1060 1585,1365,1500,1365,1200 (ArSO:I-.H*O) cm-': 'H NMR ( M e 2 s O - d ~6) 6.8-8.4(6H, m), 6.05 (1 H. d of d, Jci, = 10 Hz,J t I a n s = 16 Hz), 4.75(1H, d, Jcis = 10 Hz), 454 (1H, d, J,,,,, = 16 I&), 2.74(2H, s). Anal. Calcd for C I ? H ~ O ~ K S T HC,~44.70; O : H, 3.44.Found: C, 44.73; H. 3.35. 4-(Vinylthio)-l-naphthalenesulfonamide(16).T o a cold (ice bath) solution of 3.87g (12mmol) of 14 in 24 mL of dry DMF was added 1.7 mL (24mmol) of SOCIz. The solution was stirred for 3.5h, after which time TLC showed a major spot a t R f 0.84(benzene) plus several other minor spoi:s. The reaction mixture was poured over iceiHz0, and the oily product was extracted with benzene. The benzene layer was washed with H20, followed by saturated NaCl (aq), and dried over MgS04.Removal of the benzene on a rotary evaporator afforded 3.18g of crude 1.5 as a yellow oil which failed to crystallize. This was chromatographed on silica gel using benzene as the eluent, and the fraction containing only material of R f 0.83(benzene) was rotary-evaporated to give 2.68g (78%)of 15 as a yellow oil which was directly dissolved in 35 mL of dry acetonitrile and treated with excess NH3 gas as described in the synthesis of 9. After stirring for 1 h a t room temperature, TLC showed a major spot at Rf 0.67along with minor spots. The acetonitrile was evaporated on a steam bath, water was added, and the straw-colored solid obtained was collected, washed with water, and dried at reduced pressure to give 2.41g (97%) of crude 16,mp 143-149 "C. I3C IVMR (MezSO-ds) showed that this crude product was essentially 16 along with a small amount of unidentified impurity. Recrystallization of the crude product from 95% EtOH af-
J . Org. Chem., Vol. 43, No. 24, 1978 4661 forded 1.69g (68%) of tan crystals, mp 153.5-155.0"C. Further crystallization from 95% EtOH gave an analytical sample of 16 as buff crystals: mp 156-157 "C; TLC R f 0.70; IR (KBr) 3430 (NH), 3335 (NH), 1560,1500,1325 (ArSOTNHQ),1260,1200,1160,1140 (ArSOzNHz), 910cm-I; 13C NMR (Me2SO-de) 138.4,137.9,131.5,129.1,
128.3,128.0,127.6,126.6,126.1,125.1,124.8,119.8. Anal. Calcd for C12HllN02S2: C, 54.32;H, 4.18; N, 5.28.Found: C, 54.46;H, 4.21;N, 5.33. 4-(Vinylsulfonyl)-l-naphthalenesulfonamide (17). A. From 4-(Vinylthio)-l-naphthalenesulfonamide (16).A mixture of 0.27 g (1mmol) of 16,1.5mL of HOAc, 0.2mL of 90% HzO2, and 0.8mL of HzO was heated on a steam bath for 1 h. The resulting solution was cooled in an ice bath, and the colorless solid which crystallized was collected, washed with water, and dried to give 0.26g (87%) of 4(vinylsulfony1)-1-naphthalenesulfonamide(17)as colorless crystals: fluorescent; IR (KBr) 3430 (NH), 3340(NH), mp 15&159 "C; R f 0.53, 1540,1510,1330 (ArSOZR),1190,1160(ArSOZR),1135 (ArSOZNHz), 990 cm-I; 13C NMR ( M e z S 0 - d ~ )145.4,138.4,138.3,130.9,129.2,
128.8, 128.6, 128.4,126.5,125.3,124.8. Anal. Calcd for C12HllN04S2: C, 48.47; H, 3.73; N,4.71.Found: C, 48.36;H, 3.82;N, 4.82. B. From 4-(2-Acetoxyethylsulfonyl)-l-naphthalenesulfonamide (10).To 0.35g (1mmol) of 10was added 1.2mL of 10% NaOH (aq) and 1.2mL of HzO. A pale yellow solution resulted and, after 1 min at room temperature, the solution was added to 3 mL of 5% HC1 (aq).The white gummy precipitate that formed was washed with H20 by decantation and dissolved in MezSO-ds for a 13C NMR spectrum which showed the presence of 17 along with small amounts of impurities, none of which were either 10 or 1 as shown by the absence of upfield resonances a t 58.7,54.6,19.9(lo), or 58.1,55.2(1).The MezSO solution was added to HzO, and 0.23g (79%) of impure 17was obtained: mp 150-153 "C; TLC R f 0.50,fluorescent.
Reaction of 4-(Vinylsulfony1)-1-naphthalenesulfonamide(17) with Aqueous Sodium Hydroxide.A. A sample of 17 was dissolved NMR showed the in 5% NaOH ( a s ) and, after standing for 2 h, presence of all ten bands corresponding to an authentic sample of 1 in aqueous NaOH: I3C NMR (HzO, OH-) (sample from 17 in paren136.7(136.7), 130.5(130.41,129.9(129.81, 129.2 theses) 149.7(149.71, (129.1),127.8 (127.8), 124.9(124.91,124.5(124.51, 58.4(58.4), 56.1 (56.1). B. A sample of 17was dissolved in 6 drops of 1O0/o NaOH ( a s ) and, after standing at room temperature for 1 h, the solution was acidified with 5% HCI. The precipitate that formed was shown to be HO-ENS (1):mp 207-208 "C; TLC R f 0.12(major),0.47(trace). C. A sample of 0.15g of 17was dissolved in 2.5mL of 5% NaOH (aq). After standing at room temperature for 1 h, the solution was acidified with 5% HCI, and the precipitate was collected and dried (quant).13C NMR (MezSO-ds) showed the product to be mainly 1 with small amounts of impurity.
13CNMR Spectra of 4-Ethylsulfonyl1 -naphthalenesulfonamide (2)and 4-Ethylthio-1-naphthalenesulfonamide(18).The NMR spectra of these compounds (2 and 18) were not reported in the earlier paper2 and were determined as part of the current work for comparison purposes to allow assignment of the compounds in this paper as belonging to the ENS (2)series: 13C NMR (2)(MezSO-ds)
145.2,137.6,129.4,129.2,128.6,128.4,126.5,125.1,124.9,49.7,7.2; NMR (18)(MezSO-ds) 141.1,136.2, 131.2.128.0,127.8.127.1,126.6,
126.1,124.4,120.9, 25.5,13.6.
Acknowledgments. This work was performed under the auspices of the U S . Energy Research and Development Administration. We wish to thank Mrs. Ruby JUof the Chemistry Department, University of New Mexico, for performing the elemental analyses. Registry No.-1, 23043-35-8; 2, 842-00-2; 3, 529-36-2; 4, 172255, 67761-05-1; 7,67761-06-2; 8,67761-07-3; 8a,67774-29-2; 9, 94-4; 67784-59-2; 10, 67761-08-4; 11, 35374-48-2; 12, 67761-09-5; 13, 67761-10-8;14, 67761-11-9; 15, 67761-12-0; 16, 67761-13-1; 17, 2-chloroethanol, 107-07-3; 7 free acid, 67761-14-2; 18,28177-06-2; 67761-06-2.
References and Notes (1) L. R . A. Bradshaw, Biochem. J., 114, 33P (1969). (2) G. H. Daub and T. W. Whaley, J. Org. Chem., 41, 883 (1976). (3) T. W. Whaley and G. H.Daub, J. Labelled Compds. Radiopharm., 13, 481 (1977). (4) Available from Eastman; it was also prepared from 1-naphthalenesulfonyl chloride by reduction with zinc in acetic acid [E. Knusli, Gazz. Chim. /tal., 79, 621 (1949)]. Pyrolysis of el-naphthyl N,N-dimethylthiocarbamate
4662 J . Org. Chem., Vol. 43, No. 24, 1978
Notes
according to the method of Newrnan and Karnes [J. Org. Chem., 31,3980 (1966)] failed. (5) W. R. Kirner and G. H. Richter, J. Am. Chem. Soc., 51, 3409 (1929). (6) H. H. Bosshard, R. Mory, M. Schmid, and H. Zollinger, Helv. Chim. Acta, 42, 1653 (1959). (7) G. A. Russel and L. A. Ochryrnowycz, J. Org. Chem., 35, 2106 (1970). (8)K. L. Agarwal, M. Fridkin, E. Jay, and H. G. Khorana, J. Am. Chem. Soc., 95, 2020 (1973). (9) T. Narnbara, J. Pharm. SOC.Jpn., 74, 17 (1954); Chem. Abstr., 49, 1640e (1955). (10) W. R. Kriner and W. Windaus, "Organic Syntheses", Collect. Vol. /I, Wiley, New York, N.Y.. 1943 p 136. (11) F. Montanari, Boll. Sci. Fac. Chim. lnd. Bologna, 14, 55 (1956); Chem. Absb., 51, 5723b (19!57). (12) F. G. Bordwell and E. Id. Pitt, J. Am. Chem. SOC.,77, 572 (1955).
New Approaches 1,o t h e Pyrrolizidine Ring System: Total Synthesis of (f)-Isoretronecanol a n d (f)-Trachelanthamidine1p2 Harold W. €'innick* and Yeong-Ho Chang
of this unsaturated lactam into the key intermediate 7 requires reduction of the lactam carbonyl as well as the enamine double bond; however, direct reduction of the lactam carbonyl proves difficult. Fortunately, catalytic reduction proceeds smoothly to give lactam ester 6 which undergoes further reduction with excess lithium aluminum hydride (LiAlH4) to give isoretronecanol. Selective reduction of lactam 6 would give ethyl isoretronecanolate (7)which is reported to epimerize upon heating with base to give the more stable diastereomer 87 which will yield trachelanthamidine after reduction with LiAlH4. Several attempts to carry out this selective reduction (6 7) with diboranes were complicated by the difficulty in destroying the amine-boron complex after the reduction was complete. In every attempt much product was lost during the workup. By using phosphoryl chloride/sodium borohydrideg instead of diborane, however, this problem was circumvented and 6 was reduced to ester 7 in 66% yield. This completes a formal synthesis of trachelanthamidine.
-
Department of Chemistry, Unzuersitg of Georgia, Ai hens, Georgia 30602
Experimental Section
Rweiied Julg 18, 1978
Proton nuclear magnetic resonance spectra were recorded on a Varian T-60 instrument. Carbon 13 nuclear magnetic resonance spectra were recorded on a JEOL PFT-100spectrometer. All chemical shifts are reported in ppm downfield from tetramethylsilane (0.0) as an internal standard. Infrared spectra were recorded on a PerkinElmer Model 257 spectrometer and are reported in cm-l (calibration with 1601 cm-' polystyrene peak). Melting points were determined on a Thomas-Hoover melting point apparatus and are uncorrected. Reagent grade THF was distilled from potassium prior to use. Other anhydrous solvents were distilled from CaH2 and stored over 4A molecular sieves until use. Combustion analyses were performed by Atlantic Microlabs, Atlanta, Ga. Preparation of Thiopyrrolidone. Phosphorus pentasulfide (24.4 g, 110 mmol) and 300 mL of anhydrous xylene were mixed in a 1000-mL flame-dried three-neck flask equipped with an efficient mechanical stirrer. Pyrrolidone (42.5 g, 500 mmol) was added in one portion and the solution was allowed to stir a t room temperature for 20 min. A dark brown oil separated after the reaction mixture was heated at 130 "C for 30 min with vigorous stirring. The hot solution was filtered through a coarse sintered glass funnel. White crystals formed immediately in the filtrate. Fresh xylene (100 mL) was added to the oily residue and heated to 130 "C for 20 min followed by a hot filtration. This process was repeated once more and the combined xylene was allowed to cool. White crystals were collected by filteration and air dried to give 32.2 g (64%)of thiopyrrolidone: mp 114-115 "C (1it.j mp 114-115 "C) after recrystallization from CHCls/hexane; NMR (CHC13) 1.95-2.5 ( 2 H, m), 2.85 (2 H, unsym t, J = 8 Hz), 3.7 (2 H t, J = 8 Hz), 8.5 (1H, br s); IR (NaC1) 3415 (sharp),3120 (broad), 1547,1520 cm-' Alkylation of Thiopyrrolidone with Ethyl Bromoacetate. Ethyl bromoacetate (53.2 g, 319 mmol) was added dropwise to thiopyrrolidone (32.2 g, 319 mmol) dissolved in 250 mL of CHzC12 a t 0-10 "C. The reaction mixture was allowed to warm gradually to room temperature and was stirred for 4 h. Solid NaHC03 was added in portions until further addition did not cause COz evolution. The CHzC12 solution was washed with saturated NaHC03 and water, dried over MgSO4, and concentrated to give the thioimino ester (60.0 g, 100%): bp 115-120 "C (1.2 mm); NMR (CDC13) 1.3 (3 H, t, J = 7 Hz), 1.E-2.4 (2 H,m), 2.5-2.9 ( 2 H , m ) ,3.7-4.1 ( 4 H , m a n d s ) , 4.3 ( 2 H , q , J = 7 Hz); IR (NaCl) 2950,2850,1735,1580 cm-'. Preparation of Enamine Ester 3. The thioimino ester (60.0 g, 319 mmol), triphenylphosphine (334 g, 1.28 mol), and 550 mL of anhydrous xylene were combined in a flame-dried 1000-mL three-neck flask. A solution of KO-t-Bu (3.57g, 32.0 mmol) in 20 mL of tert-butyl alcohol was added dropwise and the reaction mixture was stirred a t room temperature for 4 h and then refluxed for 60 h. This was cooled and extracted with 150 mL of 10% HC1 three times. The combined aqueous extracts were washed with 50 mL of ether three times, neutralized with solid NaHC03, and extracted with four 100-mL portions of CH2C12. The combined CH2Clz layers were washed twice with 80 mL of brine, dried over MgS04, and concentrated to give a crude brown solid which was sublimed (40 "C, 0.1 mm) to yield 3 (37.6 g, 76%): mp 62-63 "C; NMR (CDC13) 1.25 (3 H, t, J = 7 Hz), 2.0 ( 2 H, t, J = 6 Hz), 2.6 ( 2 H, t, J = 7 Hz), 3.6 ( 2 H, t , J = 6 Hz). 4.2 (2 H, q,
The family of alkaloids containing the pyrrolizidine ring system is attracting much attention3 because of the wide range of physiological properties exhibited by these compound^.^ We report the total synthesis of the two simplest members of this series of alkaloids: the diastereomers of l-hydroxymethylpyrrolizidine, isoretronecanol ( l ) , and trachelanthamidine (2).
1
The basic strategy for the syntheses is outlined in Scheme I. Thus, pyrrolidone i:j converted into thiopyrrolidone which yields the enamine ester 3 by the two-step procedure developed by Eschenmoserj (eq 1).Reaction of compound 3 with
lithium diisopropylaniide (LDA) in tetrahydrofuran (THF) followed by ethyl bromoacetate gives the diester 4 in 74% yield.6 Cyclization with potassium hydride at 0 "C in T H F affords the lactam 5 in nearly quantitative yield. Conversion Scheme I
CO Et I
CO.Et
Cx0-GJ -wo 3
4
0 5
6
1
J H C Q J
1
-+2
8
0022-326317811943-4662$01.00/0 0 1978 American Chemical Society
